Osteoarthritis (OA) is a degenerative joint disease involving mechanical abnormalities such as joint degradation, both of the articular cartilage and bone, particularly subchondral bone. Bone changes often precede loss of cartilage. It can be caused by a variety of factors including hereditary, developmental, metabolic, and mechanical. In the latter instance, acute trauma such as damage to a joint or limb at one stage in an individual's life, can precipitate the condition at a later stage, in some instances much later i.e. 5-15 years later. Indeed, of the 95,000 anterior cruciate ligament reconstruction (ACL) operations and 38,000 arthroscopies to correct meniscal tears performed per year in the NHS, 50% of the treated patients proceed to early OA 5-15 years later. A proportion of these patients go on to need total joint replacement therapy, an extremely common and expensive procedure which is not successful in up to 20% patients undergoing knee replacement surgery. Similarly meniscal tears in the knee and tendon/ligament/disc damage in any joint predispose to joint degeneration which ultimately leads to osteoarthritis many years later.
Symptoms of OA may include joint pain, causing loss of movement, tenderness, stiffness, locking, and sometimes an effusion. Patients may also experience muscle spasm and contractions in the tendons. Occasionally, the joints may also be filled with fluid. As a result of decreased movement, adjacent muscles may atrophy, and ligaments may become more lax.
OA commonly affects the hands, feet, spine, and the large weight bearing joints, such as the hips and knees, although any joint in the body can be affected. As OA progresses, the affected joints change their shape, are stiff and painful, and usually feel better with gentle use but worse with excessive or prolonged use, thus distinguishing the disease from rheumatoid arthritis. In addition, and more profoundly, OA can be distinguished from RA on the basis that RA is an autoimmune, systemic disorder whereas OA does not involve a systemic immune response and is localised.
In smaller joints, such as the fingers, hard bony enlargements, called Heberden's nodes (on the distal interphalangeal joints) and/or Bouchard's nodes (on the proximal interphalangeal joints), may form, and though they are not necessarily painful, they do limit the movement of the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red or swollen. Some people notice these physical changes before they experience any pain.
OA is the most common form of arthritis, and the leading cause of chronic disability in the United States. It affects nearly 27 million people in the United States and about 8 million people in the United Kingdom. Knee OA is one of the most common musculoskeletal diseases, affecting almost 251 million humans. Within this population, it is particularly concerning that over 30% of patients with acute anterior cruciate ligament (ACL) or meniscal injuries develop radiographic knee OA within 5 years post-injury. Joint trauma can lead to a spectrum of acute lesions, including osteochondral fractures, ligament or meniscus tears and damage to the articular cartilage. This is often associated with intra-articular bleeding and causes posttraumatic joint inflammation. Although the acute symptoms resolve and some of the lesions can be surgically repaired, joint injury triggers a chronic remodeling process in cartilage, bone and other joint tissues that initiates inflammatory and metabolic imbalance between anabolic and catabolic processes, tissue remodeling and biomechanical changes. The interactions between these biomechanical and biochemical changes propagate the path to degenerative joint disease that ultimately leads to joint failure.
There is therefore strong evidence implicating trauma with the likelihood of developing joint degeneration and OA. Indeed, this has led to the definition of a subset of the OA disease termed post traumatic osteoarthritis (PTOA) i.e. degenerative joint disease secondary to injury that may lead to OA years later. It is particularly prevalent in young and active individuals such as those involved in sport during which there is increased risk of sustaining such injury. It can therefore be defined as the presence of a normal joint prior to injury, structural damage at the time of injury and the joint not being compromised by systemic disease (Pickering, 1984). Joint trauma affects all joint tissues leading to physiological, biomechanical and biochemical changes that may progress toward joint degeneration and subsequent development of OA.
Treatment generally involves a combination of exercise, lifestyle modification, and analgesics. If pain becomes debilitating, joint replacement surgery may be necessary to improve the quality of life. Surgical intervention is sometimes recommended after joint injury to correct abnormal joint biomechanics, reducing the risk of secondary injuries, and ideally reducing the risk of OA. Unfortunately, surgical interventions (e.g. AU reconstruction, meniscectomy, meniscal replacement) do not restore normal joint biomechanics or prevent knee OA. Therefore, it is important to understand which of these patients will develop early-onset knee OA and if this onset of knee OA can be prevented or delayed. Whilst pain management and surgery are current options, currently there are no approved therapies to address post-traumatic arthritis and its prevention. There is a clear recognition of the risk of developing OA after joint trauma, and thus there is an obvious and urgent need to develop and implement strategies that prevent post-traumatic cartilage degradation.
The amino acid glutamate is the primary neurotransmitter in the vertebrate nervous system. However, as well as afferent and sympathetic nerve terminals, glutamate is released by numerous cells in the synovial joint including macrophages, lymphocytes, synoviocytes, osteoblasts and chondrocytes. Glutamate exerts its physiological effects by binding to various GluRs which are classified into two functionally distinct categories: ionotropic (iGluR) and metabotropic (mGluR).
The iGluRs act as glutamate-gated ion channels and are separated into three distinct sub-groups based upon their pharmacology: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA). mGluRs are G protein-coupled receptors and can be divided into eight different sub-types (mGluR1-8) depending upon their structure and physiological activity. Glutamatergic signaling is regulated by five high affinity Na+-dependent excitatory amino acid transporters (EAATs): EAAT1/GLAST, EAAT2/GLT-1, EAAT3/EAAC1, EAAT4, and EAAT5. In the synovial joint, functional GluRs and EAATs are expressed by synoviocytes, osteoblasts, osteoclasts, osteocytes, chondrocytes, tenocytes, macrophages and lymphocytes.
Our recent data revealed that human fibroblast-like synoviocytes (FLS) express functional GluRs that regulate FLS release of IL-6 and proMMP2 (27).
It is known that IL-6 concentrations are significantly increased in synovial tissue and fluid from active RA patients, and correlate with radiographic joint destruction. IL-6 promotes synovitis by inducing angiogenesis, infiltration of inflammatory cells and synovial hyperplasia, causes bone resorption by inducing osteoclast formation, and cartilage degeneration by stimulating matrix metalloproteinase (MMP) expression from synovial cells and chondrocytes. Elevated IL-6 levels in RA are produced mainly by FLS, with macrophages and chondrocytes producing significant, but lower levels. The important role of IL-6 in the pathology of RA is highlighted by IL-6−/− mouse studies in which reduced severity and delayed onset of arthritis are key outcomes. Treatment of RA patients with the anti-IL-6 receptor inhibitor tocilizumab significantly improves synovitis and radiographic changes, however, these significant benefits often come with a negative impact on host immunity, as seen in IL-6 deficient mice which are unable to clear bacterial infections and mount an effective T cell memory response.
Our recent published data (Flood et al 2007) revealed that activation of NMDA receptors decreases proMMP-2 release by human RA FLS. The noncompetitive NMDAR antagonist, MK801, significantly increased proMMP-2 release in RA but not normal FLS. However, the competitive NMDAR antagonist, D-AP5 and AMPA/KA receptor antagonists, CFM-2 and NBQX, did not affect MMP-2 expression by FLS. This work shows that activation of NMDA GluRs in RA FLS is dependent upon the nature of the antagonist.
Moreover, high glutamate concentrations increased IL-6 release by RA FLS via activation of KA receptors and this was inhibited by the AMPA/KA receptor antagonist NBQX, but not the AMPA receptor antagonist, CFM-2, nor the NMDA receptor inhibitors MK801 or D-AP5. This shows the effects on IL-6 are mediated via kainate receptors, not AMPA or NMDA receptors.
We have unexpectedly since discovered that specifically the subset of AMPA and KA (AMPA/KA) GluR inhibitors have therapeutic benefit in the prevention, prophylactically, of developing OA following trauma by administering to joints at, or about, the time of injury when there is no actual evidence of OA disease. Without wishing to be limited by any biological explanation we consider that increases in synovial fluid glutamate concentrations associated with disease at the time of injury, activates AMPA/KA GluRs that, in turn, lead to bone remodeling, mechano-responses, inflammation, pain and unexpectedly degeneration. It therefore follows that such GluRs may be therapeutically targeted at the time of injury or shortly thereafter to prevent the subsequent development of, mid to long term, degenerative joint disease leading to full-blown or late stage OA.
Prior to this work, GluR antagonists in the context of arthritis, more specifically OA, have been exclusively used systemically to alleviate pain in patients with established or advanced OA disease via the effects of the drugs upon neurotransmission, and/or inflammatory pain. The pain associated with OA usually occurs very late in the degenerative process, which is why OA is inherently difficult to treat as the symptoms come after the damage has occurred. In fact, the presence of pain is part of the clinical diagnosis of arthritis. This means that treatment with a drug to prevent pain would not be given at a time when treatment with a drug to prevent OA onset/progression would be given. In fact, patients at risk of developing OA (e.g. after ACL rupture, meniscal tear, rotator cuff injury, etc) do not, by definition, have arthritis (i.e. joint space narrowing on x-ray). All work hitherto has focused on treatment of pain in patients exhibiting disease, indeed using systemic administration, as the major effects of these drugs is via their effect upon the brain and spinal cord. For example, Martel-Pelletier (2012) reports that KA receptor antagonists have a role to play in nociception and that the ionotropic glutamate receptor iGluR5 antagonist LY545694 has been tested to treat central nervous system pain in knee OA but not as a disease modifying OA drug or in patients at risk of developing OA. Furthermore, Szekely et al (1997) reported that oral administration of GYKI 52466, a non-competitive antagonist of AMPA/KA receptors in rodent arthritis induced by intraplantar injection of 0.1 ml Freund adjuvant into the right hindpaw, had no effect on primary oedema on the right paw or the secondary, generalized inflammation-induced swelling of the left paw in the second phase of the chronic disease, but attenuated hyperalgesia and body weight loss, suggesting a central effect on chronic pain. This study showed no disease modifying effects and relates to central pain mechanisms.
In contrast we have identified that: i) the direct or targeted delivery of ii) a specific subset of GluR antagonists to iii) a damaged joint iv) at the time of trauma, or shortly thereafter when there is no evidence of joint OA, significantly prevents or reduces the likelihood of developing early stage OA i.e. degenerative joint disease leading to late stage OA (i.e. the effect of the antagonists is preventative rather than curative). The invention therefore has excellent potential for preventing OA disease from ever occurring as a result of joint injury. The invention is not concerned with treating or reversing OA disease once it has become established.